REVIEW
published: 17 May 2019
Edited by:
Silvia Benvenuti,
Fondazione del Piemonte per
l’Oncologia, Istituto di Candiolo
(IRCCS), Italy
Reviewed by:
Diego Tosi,
Institut du Cancer de Montpellier
(ICM), France
Giovanni Gaudino,
Retired, Bellinzona, Switzerland
*Correspondence:
Alwin Krämer
a.kraemer@dkfz.de
Specialty section:
This article was submitted to
Molecular and Cellular Oncology,
a section of the journal
Frontiers in Oncology
Received: 14 February 2019
Accepted: 29 April 2019
Published: 17 May 2019
Citation:
Bochtler T and Krämer A (2019) Does
Cancer of Unknown Primary (CUP)
Truly Exist as a Distinct Cancer Entity?
Front. Oncol. 9:402.
doi: 10.3389/fonc.2019.00402
Frontiers in Oncology | www.frontiersin.org
doi: 10.3389/fonc.2019.00402
Does Cancer of Unknown Primary
(CUP) Truly Exist as a Distinct Cancer
Entity?
Tilmann Bochtler 1,2,3,4 and Alwin Krämer 1,3*
1
Clinical Cooperation Unit Molecular Hematology/Oncology, Department of Internal Medicine V, German Cancer Research
Center, University Hospital Heidelberg, Heidelberg, Germany, 2 Department of Thoracic Oncology, Thoraxklinik at Heidelberg
University Hospital, Heidelberg, Germany, 3 Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg,
Germany, 4 Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center for Lung Research
(DZL), Heidelberg, Germany
Cancer of unknown primary (CUP) designates an enigmatic cancer entity with histologic
confirmation of malignancy from a metastasis but no identifiable primary tumor in spite
of a thorough diagnostic work-up. In this review, we discuss the validity of CUP as
a distinct cancer entity as well as diagnostic pitfalls. As arguments against a distinct
entity, the diagnosis of CUP is erroneous in some cases. Diagnostic pitfalls include
incomplete diagnostics, uncertainty in classifying a lesion as either primary or metastasis
and mistaking a relapse of an antecedent malignancy as CUP due to histologic and
immunohistologic disparities. Given the high frequency of prior malignancies in CUP
patients, relapse of an antecedent cancer should always be carefully excluded. Gene
expression profiling-based classifier assays aim at aligning the molecular profile of CUP
patients with established primary cancer patterns for highest congruency in order to
identify the putative primary and treat accordingly. However, the spectrum of predicted
putative primaries by molecular techniques is somewhat at odds with the primaries
identified in autopsy series. Also, a first randomized clinical trial did not show superiority
of primary-tailored therapy over unspecific platinum-based chemotherapy. CUP cases
share an aggressive clinical course, atypical metastasis pattern, rapid progression of
metastases, a generally poor response to chemotherapy and dismal outcome as distinct
clinical features. Metastatic spread appears to take place in the early stages of tumor
evolution, with CUP metastases subsequently undergoing genetic evolution toward a
chromosomally highly complex and instable karyotype independent from the primary
tumor. In clinical practice, the diagnosis of CUP is valid when no primary tumor is
detectable. Treatment should ideally offer broad spectrum coverage across numerous
malignancies and be well-established in CUP as is the case for carboplatin/paclitaxel
and cisplatin / gemcitabine in particular, but it should also cover the most likely putative
primary. The diligent diagnosis of CUP is warranted for clinical trials, making the eligibility
process particularly laborious. In conclusion, we deem CUP a distinct cancer entity and
the diagnosis accurate in most patient cases.
Keywords: Cancer of unknown primary (CUP), metastasis, classifier assay, chromosomal instability (CIN), next
generation sequencing, clonal relationship, clinical trial, treatment
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Bochtler and Krämer
INTRODUCTION
Cancer of unknown primary (CUP) is an enigmatic cancer
entity. It is diagnosed in malignancies, where metastases have
been histologically confirmed, but where no primary site can be
identified in spite of a comprehensive diagnostic work-up (1–4).
When making the diagnosis, oncologists frequently meet with
incomprehension of patients and relatives, for whom a diagnosis
of CUP is hard to accept. Possible theoretical explanation
models for the CUP phenomenon like smallness of the primary
tumor that evades detection (5) or biological differences between
primary and metastases, leading to the regression of the former
and expansion of the latter are elusive and hard to grasp. The
failure to identify the primary tumor also often makes patients
question the diagnosis of malignancy per se and coping with the
cancer diagnosis even more difficult. It often fosters lingering
resentment against chemotherapy, which is unavoidably empiric
given the failure to detect the primary. Honestly, CUP specialists
do not fare better with some of their fellow oncologists (to say
nothing of pathologists), who taunt them that CUP has ceased
to exist as a valid diagnosis in the era of molecular diagnostics.
In this review, we therefore aim to put the spotlight on the
accuracy of CUP diagnosis and the validity of CUP as a distinct
cancer entity.
ARGUMENTS AGAINST CUP AS A
DISTINCT CANCER ENTITY
False or Premature Diagnoses of CUP
All oncologists in the field, who get CUP patients referred
from local hospitals, are aware that some diagnoses of CUP
are premature or even outright erroneous. Keeping obvious
misdiagnoses aside, where histologic confirmation of imaging
findings suspicious of a primary tumor is missed, there are
also cases with an incomplete diagnostic work-up. Typically,
the mandatory diagnostic standard as laid down in the
European Society of Medical Oncology (ESMO) guidelines (6)
is routinely performed: this includes a histology and meticulous
immunohistochemistry, a thorough physical examination, basic
blood, and biochemistry analyses as well as CT or MRI imaging
of the chest, abdomen and pelvis. However, further tests as
determined by clinical judgement based on the clinical picture
and the immunohistologic profile are sometimes left out. From
our own experience with patients presenting for second opinion
at our center, diagnostic efforts among centers and patients
differ widely. While the bare minimum of tests as required by
the ESMO guidelines has been performed in some patients,
many patients have received an extensive diagnostic work-up
far beyond the requirements of the ESMO guidelines. Thus
lacking or insufficient diagnostic tests might lead to an erroneous
diagnosis only in some patients. The correct diagnosis of CUP
also strongly relies on the clinical judgement and experience of
the treating oncologist.
Abbreviations: CIN, chromosomal instability; CK, cytokeratin; CUP,
cancer of unknown primary; DCC, disseminated cancer cell; TTF1, thyroid
transcription factor-1.
Frontiers in Oncology | www.frontiersin.org
Is CUP a Distinct Entity?
At least at our center, we repeatedly observe delicate cases
where a relapse of a prior malignancy has to be considered
as a differential diagnosis to a new CUP. Some patients
referred as CUP in truth suffer instead from relapse of an
antecedent malignancy which was disregarded due to histologic
or immunohistologic disparities between the two tumors. Given
a high rate of prior malignancies of around 20–25% among
CUP patients (7), the identification of cryptic relapses of an
antecedent malignancy is highly relevant in many patients. In
11 cases, we were skeptical of the CUP diagnosis and considered
relapse of the antecedent malignancy as a differential diagnosis
(7). We addressed these questionable cases by comparative
panel sequencing of both tumors to elucidate their clonal
relationship. Based on fully or largely overlapping mutational
spectra, seven out of 11 presumed CUP cases could be reclassified
as relapses of the known antecedent malignancy, whereas largely
divergent mutational patterns established clonal independence
of the tumors in four out of 11 cases and thus corroborated
the diagnosis of CUP. Interestingly, all of these four patients
harbored a germline mutation which might have played a
predisposing role in both cancers. Markedly, all patients with
overlooked relapse of a prior malignancy had been scheduled
with our CUP clinic, thus excluding clinically obvious relapse
cases. It should also be noted that in these cases histologies
of the antecedent cancer and the proposed CUP were widely
different up to situations where an adenocarcinoma in one and
a squamous cell carcinoma in the other sample was found. This
study strongly cautions against a premature diagnosis of CUP
in patients with antecedent malignancies (7). At our center,
we now have adopted a policy of parallel comparative panel
sequencing of both prior malignancy and CUP tumor to elucidate
their clonal relationship in dubious cases. Obviously, we cannot
rule out a polyclonal cancer origin as a potential pitfall when
assessing cancer relationships with this comparative molecular
panel sequencing approach (8).
Another delicate aspect is the clinical judgement
whether a malignant lesion should be classified as primary
cancer or metastatic site, thus entailing the diagnosis
of CUP. A typical example is a patient with isolated
CK7+ adenocarcinoma metastases of the liver, where
cholangiocellular carcinoma (CCC) has to be considered
as a differential diagnosis to CUP with hepatic metastases.
Likewise, a CK7+, TTF1- adenocarcinoma lung mass might
represent a primary lung cancer or alternatively a CUP with
pulmonary metastasis.
CUP With Primary Tumor Unmasked
During Disease Course or at Surgery
or Autopsy
In some CUP patients, the primary tumor unmasks itself over
time during the disease course, or is finally detected at autopsy,
ultimately leading to a revision of the CUP diagnosis. The
emergence of the primary tumor during the lifetime of the patient
is rare with frequencies in the 20% range reported in the literature
(5) and even less frequent in our experience. In contrast, the rate
of detection of the primary tumor is much higher in autopsy
2 May 2019 | Volume 9 | Article 402
Bochtler and Krämer
series, which finally demonstrate a primary in as many as 50–
80% of CUP cases, leading to a posthumous revision of the CUP
diagnosis (9–15). By autopsy, lung, large bowel and pancreas
cancers appear as the prevailing underlying primary cancers.
Hints Toward the Likely Primary by
Molecular Profiling
Advances in molecular diagnostics and microarray technology
have raised expectations that molecular profiling might provide
hints toward the likely primary tumors. For that purpose gene
expression profiling-based classifier assays have been brought
forward in CUP, which aim to align the respective profile of
a particular CUP case with the best match from previously
established profile databases from all sorts of cancer entities.
Hereby, the assignment of molecular signatures to cancers is
typically developed and validated in cancers with known primary
before the molecular profile of a CUP tumor is aligned to the
established primary pattern with the highest congruency (9).
These classifier assays can successfully identify the primary in 76–
96% of cancer cases with known primary and predict the likely
primary tumor in 83–90% of CUP specimens, assuming that the
CUP cancer has retained the basic gene expression signature
of the tissue of origin during metastatic spread (5, 9, 16, 17).
However, doubts remain about the reliability of this approach.
It lies in the very nature of CUP that no definitive verification
of the molecular classification is at hand (9). Furthermore, the
spectrum and respective frequencies of molecularly identified
likely primary cancers differ from those in autopsy series (9–15),
with breast, urothelial and colorectal primaries overrepresented
in the former and pancreas and lung cancers predominating
in the latter (Figure 1) (9). However, as a caveat the respective
autopsy and molecular studies come from different decades,
allowing for a time bias in case the spectrum of putative primaries
might have changed over the last two decades.
Current studies are investigating response to treatment
tailored to the primary predicted by classifier assays as proof-
of-principle trials. In one small study in 45 CUP patients the
identification of a putative primary tumor routinely treated
with carboplatin/paclitaxel indeed predicted an actual response
to this regimen (20). In a larger study by Hainsworth and
coworkers CUP patients were scheduled to receive site-specific
treatment based on the molecular gene expression classifier
essay. In this non-randomized trial the two thirds of patients
actually receiving assay directed therapy reached a median
overall survival of 12.5 months, which compares favorably with
historic cohorts (19). Markedly, within the study cohort patients
predicted to suffer from treatment responsive cancers indeed
displayed an improved prognosis. Accordingly, Hainsworth and
Greco have concluded that the paradigm change toward a
molecular work-up has become clinical reality (21). However,
in a large randomized phase II trial site-specific therapy based
on comprehensive gene expression profiling did not improve
prognosis as compared to empirical carboplatin/paclitaxel
chemotherapy in the comparator arm, with median overall
survival times of 9.8 vs. 12.5 months, respectively (22).
Frontiers in Oncology | www.frontiersin.org
Is CUP a Distinct Entity?
FIGURE 1 | displays the relative frequencies of (presumed) primary sites in
CUP cancers. Pooled data from 12 autopsy studies including 844 autopsies
from 1944-2000 (left) are juxtaposed to gene expression profiling data from
more than 500 patients drawn from four studies published from 2001 to 2007
(middle) and 252 patients published in 2013 (right), drawn from Loffler et al.
(18), previously adapted from (9, 19). Unfortunately, no autopsy and molecular
data are available from the same decade, so the discrepant putative primary
frequencies between the autopsy and the molecular studies might either
reflect inconsistencies between both approaches or alternatively a bias by
time decade.
In addition to gene expression profiling, Moran and
coworkers have employed epigenetic profiling by DNA
methylation profiles in the search of the presumed primary (23).
In their comprehensive approach, the experience gained from
methylation profiling in large training and validation sets from
cancer patients with known primary was used to classify 216
CUP cases. Subsequent clinical detection of the primary during
further follow-up as well as histology and immunohistology
were used to countercheck the accuracy of this approach that
identified the putative cancer of origin in 188/216 (87%) of
patients. Patients who received a chemotherapy regimen tailored
to the putative primary based on clinical and pathological
findings achieved improved overall survival, although molecular
profiling was performed only retrospectively. This study might
advocate more site-directed chemotherapies at least in cases
where clinical and/or pathological findings are suggestive of a
specific site. Together with the studies by Hainsworth et al. (19)
and Hayashi et al. (22) it remains debatable whether site-specific
chemotherapy tailored to the putative primary is beneficial.
Furthermore, as also discussed by Moran et al. (23), a CUP
tumor identified by DNA methylation profiling might still be
biologically distinct from its metastatic equivalent with a known
primary tumor.
Whereas the classifier assays discussed above fully focus on
hints toward the primary tumor, panel sequencing strategies
aim at identifying targets for molecularly driven therapies
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Bochtler and Krämer
FIGURE 2 | shows the distribution of mutational spectra in CUP patients with
adenocarcinoma and undifferentiated carcinoma types as detected in a prior
study from our group, drawn from Loffler et al. (26).
independent of the tissue of origin instead (24–27). Accordingly,
the mutational spectra in these cases usually do not give
substantial hints toward the most likely primary. For example,
mutations of TP53 are by far the most abundant mutations found
in CUP cancers (Figure 2), but this mutation is recurrently found
throughout almost any kind of malignancies, thus precluding
putative site allocation. Mutations providing definitive hints
toward the most likely primary like ALK translocations for lung
cancer are scarce in CUP.
ARGUMENTS IN FAVOR OF CUP AS A
DISTINCT CANCER ENTITY
Thoroughness of Clinical Work-Up
As discussed above at least in the German health care system
many patients have received an extensive diagnostic work-
up far in excess of the minimum requirements of the ESMO
guidelines (6). Gastroscopies and colonoscopies are almost
routinely performed in every single patient. The diagnostic work-
up also often includes PET-CT scans for CUP types where they
are not even recommended as standard of care in the ESMO
guidelines. In spite of these diagnostic efforts, the primary cancer
is not identified in most cases. From a clinical perspective, the
diagnosis of CUP is therefore confirmed even after an exhaustive
diagnostic work-up in most cases, and false diagnosis of CUP
due to lacking or insufficient diagnostic tests appears as a rare
phenomenon. Admittedly, the interpretation of results is a tricky
and error-prone process.
Distinct Clinical Features Inherent to CUP
As reviewed by Pentheroudakis et al. (9) CUP cases typically
share distinct clinical features: an aggressive clinical course,
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Is CUP a Distinct Entity?
atypical metastasis pattern and rapid progression of metastases,
a generally poor response to chemotherapy and dismal patient
outcome, with overall survival rates in the 1 year range
even in clinical trial cohorts (28–33). Whereas the primary
tumor remains clinically insignificant during the clinical course,
the disease is characterized by early and rapidly progressing
metastatic spread. Therefore, an underlying CUP-specific “pro-
metastatic” genetic signature has been postulated. In tune with
this concept, the prognosis of CUP patients is inferior to the
prognosis of cancer patients with distant metastases from a
known primary, both in general and when CUP cases with a
presumed primary are compared to the “equivalent” metastatic
disease with known primary (5, 9). Furthermore, the pattern
of metastatic spread is intriguingly distinct in CUP cases, with
a high frequency of lung, brain and bone metastases as well
as unusual metastatic sites (9). Therefore, according to this
model CUP cases appear to display a distinct natural history
and biological properties rather than being an accumulation of
diverse cancers which merely share the failure of an identifiable
primary tumor (5).
New insights into the mechanisms of metastatic seed in
cancers also provide explanatory models for the enigmatic
phenomenon of an undetectable primary tumor. Experimental
data from mammary cancer animal models imply that metastatic
spread takes place in the early stages of tumor evolution (34, 35).
In these models invasive early tumor cells, which are genetically
less evolved and display stemness features, are capable to migrate
in the blood stream as disseminated cancer cells (DCC) and
found metastases far before an overt primary cancer can be
found. Apparently, these early DCCs have the potential to switch
between migration, dormancy and proliferation programs. Once
proliferation sets in, the tendency to disseminate appears to
decline. This concept of early dissemination of tumor cells
implies subsequent independent progression of primary tumor
and metastases, which both grow under the selection pressure
of the immune system and the respective microenvironment
(36). This model of early branching of the primary tumor
and metastases evolution and their long independent trajectory
under selection pressure in different niches obviously accounts
for genetic and growth discrepancies between primary and
metastases. Seen from this angle, CUP can be regarded as
the extreme end of an independent parallel evolution where
metastases have largely outgrown the primary tumor. From
this perspective, it can also be speculated that CUPs share a
prominent early DCC phase as a unifying biologic feature.
Indeed, some findings in CUP seem to support the validity
of this model, including the clinically observed high systemic
relapse rate in CUP patients with localized disease treated by
surgery and / or radiotherapy in curative intent (37). Cytogenetic
data support this model as well (38). In a study by Pantou
and coworkers CUP tumors were shown to display advanced
cytogenetic patterns, with abnormal karyotypes harboring
numerous, complex and unbalanced cytogenetic aberrations. An
average of 15 chromosomal aberrations was found per case,
increasing to 22.6 when ploidy changes were considered as well,
which is well in excess of metastatic disease with known primary
(38). In view of chromosomal instability (CIN) as a driver of
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Bochtler and Krämer
tumor evolution this karyotypic complexity in CUP reflects the
aggressiveness of metastatic growth in this entity. Markedly,
within the study cohort the patients with massive chromosomal
changes had an even worse prognosis (38). These data were fully
corroborated by a study by Vikesa and coworkers, who also found
a high level of CIN in CUP and a correlation of karyotypic
complexity with dismal prognosis. Interestingly, alignment of
the cytogenetic profiles of CUP patients with the respective
profiles from known cancer entities in this study showed that
CUPs were more distantly related to the predefined tumor classes
than metastases from known primaries. Interestingly, this equally
applied to CUP cases with the primary cancer identified or still
elusive during the further clinical course (39). Accordingly, the
authors concluded firstly that CUP exhibits distinct molecular
features, and secondly that CIN facilitates primary tumor
independent progression of metastatic sites in CUP following
early dissemination and leading to poor outcome (39).
Spontaneous tumor regressions have been reported
throughout a variety of malignancies, which are attributed
to tumor cell elimination by the immune system in view of
the frequent association with infections observed in these
cases. The concept of immune-mediated cancer surveillance is
further supported by an increased cancer incidence in transplant
recipients on immunosuppressants and the recent success of
immune checkpoint inhibitors in numerous cancer entities.
Thus, it is possible that the lack of a primary tumor in CUP is an
immune mediated event at least in some cases as well. Recently,
it was demonstrated across several cancer entities that a high
degree of CIN confers resistance to immune mediated therapies
(40). Therefore, it can be speculated that the particularly high
degree of CIN in CUP metastatic sites makes CUP tumors
resistant to immune surveillance, whereas the corresponding less
chromosomally instable primary tumors have regressed.
Interestingly, evidence suggests that primary tumors in
general actively modify future metastatic sites by tumor-
secreted factors to make them susceptible to metastatic seed,
a phenomenon called “premetastatic niche formation” (41,
42). It could be hypothesized that in CUP cases seeding
tumor cells are sufficiently aggressive themselves, allowing for
metastasis formation independent from this facilitation by the
primary tumor.
Limitations of Molecular Profiling
In spite of unquestionable progress, mutational profiling of CUP
has its limitations. Nowadays, panel sequencing is increasingly
performed on a routine basis (24–27, 43). However, as discussed
above the mutational profile obtained by these panel sequencing
approaches typically does not permit to draw conclusions
regarding the tissue of origin. In CUP, TP53 mutations are by
far most abundant (Figure 2). Given that TP53 mutations are
found throughout all types of carcinomas this does not permit
conclusions regarding a putative primary site. Likewise, other
frequent mutations in CUP including RAS, CDKN2A, MYC,
ARID1A, PIK3CA, or BRAF are not tissue specific.
The classifier assays discussed above, although designed to
detect the putative primary, have not established themselves
in clinical routine so far. None of these tests is either
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Is CUP a Distinct Entity?
marketed or insurance-covered in Germany nor are these
procedures recommended in the ESMO clinical guidelines for
CUP diagnostics and treatment (6).
Last but not least, no molecular profiling test can substitute
for a clinically identified primary tumor. Even putting aside
the disquieting frequency of discrepancies in the distribution of
primary sites between autopsy and molecular profiling patient
series (Figure 1), a CUP tumor with a distinct molecular profile
suggestive of a primary cancer behaves biologically most likely
still different from the respective primary cancer. Therefore, in
the final conclusion of two insightful reviews, Pentheroudakis
et al. judge that in view of lacking proof of prognostic benefit and
of methodological uncertainties, molecular profiling has not (yet)
become the benchmark for CUP primary detection (9, 44).
CLINICAL REALITY—VALID DIAGNOSIS OF
CUP AND JUSTIFIED ASSUMPTION OF A
PUTATIVE PRIMARY TUMOR
In most cases, the CUP diagnosis is correct, because metastatic
spread has been histologically confirmed and a primary tumor
has remained elusive in spite of a thorough work-up according to
the ESMO guidelines (6), thereby meeting the criteria how CUP
is defined. At the same time, in many patients the clinical picture
along with the histologic, immunohistologic and molecular
profile is suggestive of a putative primary. Nevertheless, the
diagnosis of CUP remains valid as long as no primary tumor in
the respective organ is detectable.
For reasons described above, in cases with a putative
primary, treatment should follow the treatment algorithms for
the suspected primary cancer. For example, if a patient is
diagnosed with a CK20+, CDX2+, CK7– adenocarcinoma with
liver and peritoneal metastases, both the immunohistologic
profile and the distribution of metastatic sites is in tune
with colorectal cancer, and treatment should be administered
according to protocols for metastatic colorectal cancer (45–47).
Likewise, a patient with squamous cell carcinoma of cervical
lymph nodes probably suffers from head and neck cancer
and should be treated accordingly (48–50). These two distinct
clinical constellations highly suggestive of a putative primary and
requiring specific site-directed therapy are—along with others—
accounted for in the ESMO CUP guidelines as specifically defined
favorable subsets (6). Even in entities not listed as distinct
favorable subtypes in the ESMO classification, as is the case
for CK7+ TTF1+ carcinomas in patients with mediastinal or
hilar lymph nodes or pleural carcinosis, the treatment should
be dictated by the most likely primary, in this case lung
cancer. Even in cases where the clinical suspicion is less clear-
cut – for example in cases of an immunohistologic profile
suggestive of gastrointestinal cancer, many oncologists would
prefer a gastrointestinal protocol like FOLFOX, FLO or FLOT
over empiric standard CUP chemotherapy with carboplatin /
paclitaxel or cisplatin/gemcitabine (30, 32, 33, 51). In conclusion,
the treatment should ideally offer broad spectrum coverage
across numerous malignancies and be well-established in CUP
as is the case for carboplatin/paclitaxel and cisplatin/gemcitabine
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Bochtler and Krämer
in particular, but it should also cover the most likely putative
primary. Obviously, in sophisticated cases pros and cons must
be deliberated and decisions will also depend on the preferences
of the treating oncologist. Nevertheless, even when oncologists
deem circumstantial evidence sufficient to recommend treatment
tailored to the putative primary, the diagnosis of CUP is still
valid as long as the primary tumor cannot be nailed down. We
are aware that there is a twilight zone between circumstantial
hints pointing toward a putative primary but still compatible
with the diagnosis of CUP, and unequivocal evidence for the
primary tumor.
CLINICAL TRIALS—IMPORTANCE OF
PRECISE CUP DIAGNOSIS AND NEED FOR
FURTHER STANDARDIZATION
Data from clinical trials in CUP are scarce (28, 29), with
only few phase II studies (30–32, 52–54) and a single phase
III study (55). Additionally, these clinical trials struggled with
patient recruitment, partly leading to premature study closure
prior to the recruitment of the targeted patient number. Also,
patient cohorts are heterogeneous and thus not fully comparable,
with favorable subtypes included in some studies but not
in others. In daily clinical practice, when a primary is not
confirmed but clinically likely due to the clinical picture and
the immunohistologic profile, it is absolutely sound to make
the diagnosis of CUP and to treat the patient tailored to the
putative primary. However, it is highly questionable whether
such patients should be eligible for a clinical CUP trial. This
concern applies in particular to cases where the standard empiric
CUP chemotherapy regimens (28–32, 53, 54) provided in the
respective trials do not fully match with the treatment required
for the likely primary.
There is broad consensus that the ESMO guidelines (6) should
be applied for clinical trials. However, they leave room for
interpretation. Consensus guidelines for clinical trials in CUP
have not been defined so far, and likely would also not be able
to unequivocally define the “typical” picture of unfavorable CUP
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CONCLUSIONS
CUP cases are biologically characterized by early and aggressive
metastatic spread, poor response to chemotherapy and poor
prognosis, which has led to the postulation of a unifying
underlying pro-metastatic signature in CUP.
In the era of molecular work-up further tools beyond
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characterize cancers. CUP classifier assays have been developed
which determine the putative tissue of origin of a CUP cancer
by alignment with molecular profiles established for cancers with
known primary. Even if the molecular signature points toward a
putative primary tumor, the diagnosis of CUP remains still valid
as long as no primary tumor is detectable. However, molecular
analysis, immunohistochemistry and clinical picture should
weigh in to adjust treatment to the putative primary. It remains
at the discretion of the treating physician to weigh clinical,
immuno-histochemical, and increasingly molecular findings
as well.
Some patients receive a diagnosis of CUP prematurely
and the diagnosis should always be questioned by an
experienced oncologist. Relapse of a prior malignancy should be
meticulously excluded.
Being committed and dedicated to advancing research in the
field of CUP, we as authors admit to be biased. Nevertheless, we
feel that CUP appears as a valid cancer entity and that most,
though not all, patients diagnosed with CUP indeed suffer from a
“true” CUP.
AUTHOR CONTRIBUTIONS
Both authors listed have made a substantial, direct and
intellectual contribution to the work, and approved it
for publication.
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6aa89
Conflict of Interest Statement: Both authors work as study oncologists for the
CUPISCO trial, which is sponsored by Roche, and have received reimbursement
for study related travels as well as remuneration for their work as study oncologists
for the benefit of their employer.
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author(s) and the copyright owner(s) are credited and that the original publication
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